Attention-Deficit/Hyperactivity Disorder (ADHD) is the most common neurobehavioral disorder diagnosed in childhood and adolescence and one of the most prevalent health problems afflicting school-age children. ADHD often spans the lifecycle from preschool to adulthood. One of the primary treatment modalities is pharmacotherapy. Medications include the psychostimulants (STIMs), methylphenidate (MPH) and amphetamine (AMP), and newer non-STIMs atomoxetine (ATM) and modafinil (MDF). Major limitations exist regarding short and long-term use of these agents including non-response, adverse drug effects (ADEs), unknown toxicities including recent cardiovascular risk, sex/age differences in pharmacokinetics (PK)/pharmacodynamics (PD), drug-drug interactions, and abuse potential. The ability of drug transporters to influence drug PK and PD is increasingly appreciated. Little data exist on the influence of transporters on the ADHD medications. In vitro and in vivo studies are proposed to support a long-range goal of improving the outcome and safety of ADHD therapy. This application is a translational approach addressing specific needs outlined in PA-06-379 (Developmental Psychopharmacology) and follows exploratory grant obtained through this PA (R21HD04447810-01). The transporter P-glycoprotein does not play a significant role in MPH or AMP PK, or likely, ATM and MDF but preliminary data have led to the hypothesis that one or more organic cation transporters (OCTs), located in major organs including brain and BBB are responsible for the transport of AMP and other ADHD agents. The modulation of OCTs by concomitant therapy or genetic polymorphisms could alter drug PK/PD within resulting in ADEs or toxicities. The Specific Aims are: (1) To determine if ADHD agents AMP, MPH, ATM, or MDF are substrates of OCTs1-3 (2) To determine if inhibitors of OCTs1-3 influence the transport of AMP, MPH, ATM, or MDF using in vitro and in vivo models (3) To perform a series of in vivo studies in both male/female wildtype and Oct1-3 knockout mice assessing the effect of age, and OCT inhibition on AMP, MPH, ATM, or MDF PK and PD. The proposed studies offer the potential to improve pharmacotherapy by i) supporting clinical studies in which genotyping of transporter polymorphisms may guide drug selection and dosage, ii) identify sources of interindividual variability, iii) explain ADEs and drug interactions, and iv) define sex and age differences.